Our laboratory has focused on the mechanisms through which toxic inhaled particles such as asbestos and silica cause progressive interstitial fibrosing lung disease. Using rats and mice, we have shown that inhaled particles are deposited initially at the bifurcations of alveolar ducts and that macrophages are attracted to these sites of deposition through activation of chemotactic complement proteins on alveolar surfaces. A clear interstitial lesion develops at the bifurcations within 48 hr. after a one-hr. exposure to chrysotile asbestos and progresses for at least one month post-exposure. We showed that as a result of exposure to particulates, lung macrophages produce arachidonic acid (AA) metabolites and growth factors for lung fibroblasts. We carried out a series of experiments using high performance liquid chromatography to show that AA metabolites of both the cyclooxygenase and lipoxygenase pathways are released by alveolar and intravascular macrophages. The metabolites include several prostaglandins, HETEs and leukotriene B4. The biological role of potential inflammatory and vasoactive mediators currently is being investigated. Another potential mediator of pulmonary fibrosis was found to be secreted by macrophages. This factor is similar to platelet-derived growth factor (PDGF) in several ways: molecular weight (approximately 25 KD), acid and heat stability, ability to induce quiescent fibroblasts into a "competent" state to complete the cell cycle, and inhibition of growth promoting activity by an antibody against the c-sis oncogene which codes for PDGF. We now have developed a quantitative immuno-enzyme competitive inhibition assay which detects as little as 1 ng of PDGF in serum and platelet poor plasma. Ongoing studies are directed toward quantifying the amounts of PDGF-like activity in macrophage-conditioned medium and cell-free fluids recovered from the lungs of asbestos-exposed animals. We postulate that interstitial lung macrophages synthesize and secrete PDGF-like factors which cause fibroblasts to proliferate as a consequence of exposure to fibrogenic particles. Future work is directed toward testing this hypothesis.